1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy

Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1α

Economical Optimum Gas Allocation Model Considering Different Types of Gas-Lift Performance Curves

The traditional optimum modes of gas-lift production are usually established by taking the injected gas rate as a decision variable and maximum oil production as the objective function. After solving the model, the injected gas rates of single wells are obtained, and then the oil productions of single wells, the total oil productions of well groups and economic profit can be obtained. However, the models do not take both different types of gas-lift performance curves (GLPCs) and the cost factors of gas-lift production technique into account. On the basis of GLPCs, this paper introduces the factors of a gas-lift production technique, which includes the water cut of crude oil, cost of gas injection and water treatment, and oil and gas prices. The concept of a gas-lift economic performance curve (GLEPC) is proposed, and an optimum gas allocation model is established, considering different types of GLPCs and taking economic benefits as the objective, and the model is solved by the method of mixed penalty function. Taking gas-lift well group JD as an example, four gas-lift gas allocation schemes are obtained, and the proposed economical optimum model is applied to optimize gas allocation and analyze profit. What is more, the oil production rate and the result of optimum gas allocation taking maximum oil production rate as the objective in the model are calculated and compared. Then the gas allocation scheme with maximum economical profit is selected, and the significance of considering different types of GLPCs and taking economic benefits as the objective to gas allocation is confirmed

Economical Optimum Gas Allocation Model Considering Different Types of Gas-Lift Performance Curves

The traditional optimum modes of gas-lift production are usually established by taking the injected gas rate as a decision variable and maximum oil production as the objective function. After solving the model, the injected gas rates of single wells are obtained, and then the oil productions of single wells, the total oil productions of well groups and economic profit can be obtained. However, the models do not take both different types of gas-lift performance curves (GLPCs) and the cost factors of gas-lift production technique into account. On the basis of GLPCs, this paper introduces the factors of a gas-lift production technique, which includes the water cut of crude oil, cost of gas injection and water treatment, and oil and gas prices. The concept of a gas-lift economic performance curve (GLEPC) is proposed, and an optimum gas allocation model is established, considering different types of GLPCs and taking economic benefits as the objective, and the model is solved by the method of mixed penalty function. Taking gas-lift well group JD as an example, four gas-lift gas allocation schemes are obtained, and the proposed economical optimum model is applied to optimize gas allocation and analyze profit. What is more, the oil production rate and the result of optimum gas allocation taking maximum oil production rate as the objective in the model are calculated and compared. Then the gas allocation scheme with maximum economical profit is selected, and the significance of considering different types of GLPCs and taking economic benefits as the objective to gas allocation is confirmed

Simulation Experiment and Mathematical Model of Liquid Carrying in the Entire Wellbore of Shale Gas Horizontal Wells

Shale gas is mostly produced using horizontal wells, since shale gas reservoirs have low porosity and permeability. It is challenging to predict a horizontal well’s critical liquid-carrying gas flow rate because horizontal wells have more complicated well structures and gas–liquid two-phase pipe flows than vertical wells. In addition, there are significant differences between shale gas reservoirs and conventional natural gas reservoirs as well as dynamic changes in the liquid production rate. The majority of critical liquid-carrying models currently in use in engineering are based on the force analysis of droplets in the gas stream or liquid film on the pipe wall in annular-mist flow in the vertical wellbore. However, they do not take into account the impact of changes to the entire wellbore structure and dynamic changes in the liquid production rate on gas–liquid two-phase flow patterns and liquid carrying in the wellbore. In order to perform the critical gas velocity test for liquid carrying in the entire wellbore of horizontal wells, a visual liquid-carrying simulation experimental device for the entire wellbore of horizontal wells and a high-speed camera were used in this study. The onset of liquid accumulation was analyzed comprehensively according to the overall increase of the wellbore liquid and the change of the system pressure. A modified K–H wave theory liquid-carrying model was developed by taking into account the impacts of liquid production rate and well inclination angle based on the experimental data, the K–H wave theory, the cross-section actual gas velocity, and the angle correction correlation formula. The improved liquid-carrying model is in good accordance with the test findings, according to the experimental results. In Shunan Gas Mine, Sichuan, China, there are eight deep shale gas wells, which produced a total of 25 sets of tests. The modified model was used to forecast and diagnose the liquid-carrying capacity in the entire wellbore of these wells. The diagnosis results are in good agreement with the actual production situation, and the coincidence rate is 92%

A Wideband High-Gain Dipole with Impedance and Field Control Structures

Dipoles are favorable in various applications because of their simple and light structure. However, narrow bandwidths and low gain values limit their usage in wideband and long-range systems. To solve this problem, this paper presents a new method to achieve wideband high-gain for dipoles with embedded double-sleeve and a bathtub-shaped cavity. The double-sleeve adjusts the dipole’s impedance and enforces wideband matching from 4.8 GHz to 9.4 GHz. Furthermore, the bathtub-shaped cavity reshapes the antenna’s radiation field and elevates the antenna’s boresight gain to be above 10 dBi in the bandwidth of 5 GHz to 9.4 GHz, which is a 7.75 dBi improvement over the 2.15 dBi gain of conventional dipoles. The combination of the two structures creates a wideband high-gain dipole that features an average simulated boresight realized gain of 11.8 dBi in the impedance bandwidth of 64.8%. Thus, the new antenna can work efficiently in wideband and long-range systems because of its enhanced bandwidth and gain performances

Integrated development optimization model and its solving method of multiple gas fields

To optimize production schedule and production plan of multiple gas fields with certain amount of investment and constraints and to maximize their economic benefits under the production sharing contact (PSC) mode, a quantitative relationship was applied to describe the production performance depending on the development status of multiple gas fields in China and abroad. Furthermore, with the PSC-based net present value (NPV) as the objective function, a mixed integer nonlinear programming model for gas fields with optimized production schedule and productivity was established. An adaptive layer-embedded genetic algorithm was proposed to solve this model. Through handling the variables and constraints for solving this model and improving the genetic structure, genetic operators and termination conditions of standard genetic algorithm, modeling and solving techniques were formed for integrated and efficient development of multiple gas fields. Results obtained by three methods, i.e. multi-scheme comparison without mathematical model, standard genetic algorithm which induces penalty function to treat constraints, and adaptive layer-embedded genetic algorithm, were compared. The proposed optimization model is accurate, and the proposed layer-embedded genetic algorithm provides satisfactory convergence and calculation rate, ensuring that multiple gas fields could be exploited orderly. Key words: multiple gas fields, gas field integrated development, economic benefits, development optimization model, layer-embedded genetic algorith

Transient Pressure and Temperature Analysis of a Deepwater Gas Well during a Blowout Test

On one hand, a blowout test can clean the bottom of the well, and on the other, it can learn the productivity of the well, which is important work before putting the well into production and also the main basis for production allocation of the well. The accurate prediction of the blowout test process provides a theoretical basis for the design of a reasonable blowout test system and the determination of well cleaning time. During deepwater blowout tests, gas and liquid flows are unsteady in pipes, and flow parameters change over time. At present, accurately predicting changes in fluid temperature, pressure, liquid holdup, and other parameters in a wellbore during an actual blowout process using the commonly used steady-state prediction methods is difficult, and determining whether a test scheme is reasonable is impossible. Therefore, based on the conservation of mass, momentum, and energy during the blowout test process, in this study, formation, wellbore, and nozzle flows were coupled for the first time, and a time and space of unsteady pressure drop and a heat transfer differential equation system was established; furthermore, using the Newton–Raphson method, the equations were solved. Finally, the simulation of the transient flow of the blowout test was completed. Considering a measured deepwater gas well A as an example, the blowout test process was simulated, and the variations in the wellbore flow parameters were analyzed. Comparing the simulation result with the test data, we concluded the following. (1) During the blowout process, the wellbore temperature gradually increased; pressure at the bottom of the wellbore decreased; and pressure at the wellhead increased; and (2) the established model agreed well with the actual production data, and the average error of the wellhead pressure and temperature was less than 5%. Considering the high production capacity of deepwater gas wells, the use of large-sized tubing and nozzles to spray is recommended, which can improve the speed of clearing wells and prevent the formation of hydrate

Whole-Genome Expression Analysis and Signal Pathway Screening of Synovium-Derived Mesenchymal Stromal Cells in Rheumatoid Arthritis

Synovium-derived mesenchymal stromal cells (SMSCs) may play an important role in the pathogenesis of rheumatoid arthritis (RA) and show promise for therapeutic applications in RA. In this study, a whole-genome microarray analysis was used to detect differential gene expression in SMSCs from RA patients and healthy donors (HDs). Our results showed that there were 4828 differentially expressed genes in the RA group compared to the HD group; 3117 genes were upregulated, and 1711 genes were downregulated. A Gene Ontology analysis showed significantly enriched terms of differentially expressed genes in the biological process, cellular component, and molecular function domains. A Kyoto Encyclopedia of Genes and Genomes analysis showed that the MAPK signaling and rheumatoid arthritis pathways were upregulated and that the p53 signaling pathway was downregulated in RA SMSCs. Quantitative real-time polymerase chain reaction was applied to verify the expression variations of the partial genes mentioned above, and a western blot analysis was used to determine the expression levels of p53, p-JNK, p-ERK, and p-p38. Our study found that differentially expressed genes in the MAPK signaling, rheumatoid arthritis, and p53 signaling pathways may help to explain the pathogenic mechanism of RA and lead to therapeutic RA SMSC applications